Blimp1-mediated repression of negative regulators is required for osteoclast differentiation

Abstract

Regulation of irreversible cell lineage commitment depends on a delicate balance between positive and negative regulators, which comprise a sophisticated network of transcription factors. Receptor activator of NF-κB ligand (RANKL) stimulates the differentiation of bone-resorbing osteoclasts through the induction of nuclear factor of activated T cells c1 (NFATc1), the essential transcription factor for osteoclastogenesis. Osteoclast-specific robust induction of NFATc1 is achieved through an autoamplification mechanism, in which NFATc1 is constantly activated by calcium signaling while the negative regulators of NFATc1 are suppressed. However, it has been unclear how such negative regulators are repressed during osteoclastogenesis. Here we show that B lymphocyte-induced maturation protein-1 (Blimp1; encoded by Prdm1), which is induced by RANKL through NFATc1 during osteoclastogenesis, functions as a transcriptional repressor of antiosteoclastogenic genes such as Irf8 and Mafb. Overexpression of Blimp1 leads to an increase in osteoclast formation, and Prdm1-deficient osteoclast precursor cells do not undergo osteoclast differentiation efficiently. The importance of Blimp1 in bone homeostasis is underscored by the observation that mice with an osteoclast-specific deficiency in the Prdm1 gene exhibit a high bone mass phenotype caused by a decreased number of osteoclasts. Thus, NFATc1 choreographs the determination of cell fate in the osteoclast lineage by inducing the repression of negative regulators as well as through its effect on positive regulators.B lymphocyte induced maturation protein 1 | nuclear factor of activated T cells c1 | osteoclastogenesis | transcription | bone

Identification and expression profiles of prdm1 in medaka Oryzias latipes

“…However, no observation of prdm1a was in the primordial germ cells (PGCs) of medaka. These results hinted that medaka Prdm1a possibly has similar function as its homologues of zebrafish and mouse in development of muscle [38,46], neural crest [41,46], branchial arches [46], fin [43,44,46], eye [29,55], intestine [30,31], heart [28] and bone [56]. In mouse, Prdm1 plays its role itself and/or through its partner factors, Prmt5 and/or Groucho proteins [9,25].…”

Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

“…Osteoclast differentiation. Murine bone marrow cells derived from C57BL/6 mice (5 ϫ 10 4 cells per well of a 96-well plate) cultured with macrophage colony-stimulating factor (M-CSF) (10 ng/ml; R&D Systems) for 2 days were used as monocyte/macrophage precursor cells (bone marrow-derived macrophages [BMMs]), which were further cultured for 3 days with RANKL (70 ng/ml; PeproTech) and M-CSF (10 ng/ml) with or without LA-01 (10 nM) (31). The number of viable cells among cells treated with LA-01 for 3 days was Ͼ95% of the number of viable cells among those treated with vehicle.…”

Interferon-α Acts on the S/G2/M Phases to Induce Apoptosis in the G1 Phase of an IFNAR2-expressing Hepatocellular Carcinoma Cell Line

“…Replication-defective retroviruses were generated by transient transfection of pMX-IFNAR2 or pMX-IRES-Puro (control) into PLAT-A cells using FuGene 6 reagent (Promega, Tokyo, Japan) (15). HuH7 cells were transduced with the resulting retroviruses as described previously (16) and positively selected and expanded in the presence of 2 g/ml puromycin. mAG-hGeminin mKO2-hCdt1 (kindly provided by Dr. Miyawaki, RIKEN-BSI, Japan) was cloned into the lentiviral vector CSII-EF-MCS (kindly provided by Dr. Miyoshi, RIKEN-BRC, Japan) and transfected into HEK293T cells with packaging plasmids (17).…”